Dolores Malaspina

Telomere length and early trauma in schizophrenia

BACKGROUNDnChildhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects.nnnMETHODSnThe early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR.nnnOUTCOMESnCases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91±0.74 and 1.83±0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fishers R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma.nnnINTERPRETATIONnThis data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field.

Enhancing Psychosis-Spectrum Nosology Through an International Data Sharing Initiative

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation.

Contribution of rare copy number variants to bipolar disorder risk is limited to schizoaffective cases

Background Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. BD subtypes schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I) and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania and depression. The factors contributing to the combination of symptoms within a given patient are poorly understood. Methods Rare, large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis], 1436 BD II, 579 SAB) and 8656 controls. Measures of CNV burden were integrated with polygenic risk scores (PRS) for schizophrenia (SCZ) to evaluate the relative contributions of rare and common variants to psychosis risk. Results CNV burden did not differ in BD relative to controls when treated as a single diagnostic entity. Burden in SAB was increased compared to controls (p-value = 0.001), BD I (p-value = 0.0003) and BD II (p-value = 0.0007). Burden and SCZ PRS were higher in SAB compared to BD I with psychosis (CNV p-value = 0.0007, PRS p-value = 0.004) and BD I without psychosis (CNV p-value = 0.0004, PRS p-value = 3.9 × 10−5). Within BD I, psychosis was associated with higher SCZ PRS (p-value = 0.005) but not with CNV burden. Conclusions CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Serum zinc levels in acute psychiatric patients: A case series

Zinc dysregulation is linked to neuropsychiatric disorders and a beneficial response to zinc supplementation has been demonstrated for depression. In this case series, we examined serum zinc levels with respect to clinical factors among 20 acutely ill psychiatric cases admitted to a large urban public hospital. The results showed frank clinical zinc insufficiency in a quarter of the subjects. Group-wise analyses showed a significant association between reduced serum zinc and diagnosis of depression, and reduced serum zinc in those with aggressive, assaultive, or violent behaviors. By contrast, relatively elevated zinc levels were observed in a subset of psychotic cases on antipsychotics and mood stabilizers who had no mood symptoms. In summary, clinical zinc insufficiency was common in these acutely admitted psychiatric cases. Zinc supplementation may ameliorate symptoms in certain cases and should be considered in treatment planning. A separate patient group had elevated zinc levels, which could conceivably be pathogenic. Larger studies are needed to confirm and extend this pilot data.

Sex differences in hedonic judgement of odors in schizophrenia cases and healthy controls

The neurocircuitries subserving affective and olfactory processes overlap, are sexually dimorphic, and show disruptions in schizophrenia, suggesting their intersection may be a window on the core process producing psychosis. This study investigated diagnostic and sex differences in hedonic judgments of odors and smell identification in 26 schizophrenia cases and 27 healthy controls. Associations between olfaction measures and psychiatric symptoms were also examined. Cases and controls had similar identification accuracy of unpleasant odors, but cases were significantly less accurate in naming pleasant odors. In cases, greater negative symptom severity was related to abnormal hedonic judgments; specifically, higher pleasantness ratings for unpleasant odors and higher unpleasantness ratings for pleasant odors. Greater positive symptom severity was associated with lower pleasantness ratings for neutral odors. Regarding sex differences, male cases and female controls rated pleasant odors as significantly more unpleasant than male controls. Correlations between depression severity and pleasantness ratings of neutral odors were in opposite directions in male and female cases. These results suggest that a normal sexual dimorphism in the circuitry for hedonic odor judgments may interact with schizophrenia pathology, supporting the utility of olfactory hedonics as a sex-specific biomarker of this pathology.

A pilot study assessing retinal pathology in psychosis using optical coherence tomography: Choroidal and macular thickness

Mounting evidence supports a genetic-vascular-inflammatory etiology of schizophrenia. The retina provides an indirect assessment of inflammation and degeneration in the brain. In particular, the use of spectral domain optical coherence tomography (SD-OCT) has emerged as a powerful tool for examining single retinal nerve cell layers and the choroid, the vascular layer supplying the outer retina. In this study, choroidal and macular thicknesses were measured in six patients with psychosis with either schizophrenia or bipolar disorder, and in 18 age- and sex-matched healthy controls. Mean choroidal thickness was reduced in psychosis, though not significantly so. There was a statistically significant decrease in macular thickness in psychosis patients predominantly affecting the inner layers of the macula. Significant macular thinning may signal vascular, inflammatory, or degenerative processes that may also be occurring in the brain. This is one of the first studies to examine choroidal thickness in psychosis. Further studies are needed to determine whether the retinal changes in psychosis are correlated with microvascular dysfunction, neuroinflammation, and neurodegeneration.

Independence of diabetes and obesity in adults with serious mental illness: Findings from a large urban public hospital

OBJECTIVEnThere is limited research on metabolic abnormalities in psychotropic-naïve patients with serious mental illness (SMI). Our study examined metabolic conditions in a large, ethnically diverse sample of psychotropic-naïve and non-naïve adults with SMI at an urban public hospital.nnnMETHODSnIn this cross-sectional study of 923 subjects, the prevalences of hyperglycemia meeting criteria for type 2 diabetes mellitus (T2DM) based on fasting plasma glucose and obesity defined by BMI and abdominal girth were compared across duration of psychotropic medication exposure. Multiple logistic regression models used hyperglycemia and obesity as dependent variables and age, sex, race/ethnicity, and years on psychotropics as independent variables.nnnRESULTSnPsychotropic-naïve patients, including both schizophrenia and non-psychotic subgroups, showed an elevated prevalence of hyperglycemia meeting criteria for T2DM and a decreased prevalence of obesity compared to the general population. Obesity rates significantly increased for those on psychotropic medications more than 5 years, particularly for patients without psychosis (BMI: aORu202f=u202f5.23 CIu202f=u202f1.44-19.07; abdominal girth: aORu202f=u202f6.40 CIu202f=u202f1.98-20.69). Women had a significantly higher obesity rate than men (BMI: aORu202f=u202f1.63 CIu202f=u202f1.17-2.28; abdominal girth: aORu202f=u202f3.86 CIu202f=u202f2.75-5.44). Asians had twice the prevalence of hyperglycemia as whites (aORu202f=u202f2.29 CIu202f=u202f1.43-3.67), despite having significantly less obesity (BMI: aORu202f=u202f.39 CIu202f=u202f.20-.76; abdominal girth: aORu202f=u202f.34 CIu202f=u202f.20-.60). Hispanics had a higher rate of obesity by BMI than whites (aORu202f=u202f1.91 CIu202f=u202f1.22-2.99).nnnCONCLUSIONSnThis study showed disparities between obesity and T2DM in psychotropic-naïve patients with SMI, suggesting separate risk pathways for these two metabolic conditions.

Rare missense coding variants in oxytocin receptor (OXTR) in schizophrenia cases are associated with early trauma exposure, cognition and emotional processing

BACKGROUNDnOxytocin is a peptide hormone that influences the integration of social cognition with behavior and affect regulation. Oxytocin also prominently directs the transition of neuronal GABA neurotransmission from excitatory to inhibitory after birth. The oxytocin receptor (OXTR) is linked to schizophrenia, a heterogeneous syndrome. Relationships of OXTR polymorphisms with specific clinical features could aid in evaluating any role of oxytocin in the pathogenesis of schizophrenia.nnnMETHODnSchizophrenia cases with rare missense coding OXTR single nucleotide variants (SNVs) were identified from a well-characterized sample of cases and controls who were assessed for symptoms, cognition and early life trauma.nnnRESULTSnFive of 48 cases showed rare OXTR variants. Compared to the other cases they had less severe negative symptoms (deficits in emotional expression and motivation) and less severe general psychopathology scores (depression and anxiety). They demonstrated lower nonverbal (performance) than verbal intelligence due to deficient perceptual organization and slow processing speed. They also reported greater early trauma exposure (physical and sexual abuse and emotional trauma).nnnCONCLUSIONnCases carrying rare OXTR SNVs had less negative and affective symptoms than other cases, but similar psychotic symptoms, along with specific cognitive deficits. The clinical characterization of these cases occurred in association with environmental exposure to early trauma, especially sexual abuse, which may have influenced the expression of schizophrenia in subjects harboring specific SNVs in the OXTR.

Identification of diabetes risk in dental settings: Implications for physical and mental health

ABSTRACT The risk for diabetes is significantly elevated in persons who are older, overweight, and have serious mental illness. However, primary care practitioners (PCP) tend to underestimate this risk. Although there are few opportunities for early detection of diabetes, blood exuded during routine oral exams in dental settings can be used to assess glycated hemoglobin (HbA1c) levels. The current study sought to understand how primary care practitioners would react to patients who screened positive for elevated HbA1c, how they estimated risk, and whether they provided treatment recommendations or counseling. Semistructured telephone interviews were conducted on 61 subjects three months after demonstrating elevated HbA1c levels from dental screenings. Data were transcribed and analyzed using content analysis. Qualitative analyses revealed the following four themes according to patients: (1) “Being told I needed to make lifestyle changes” (41%); (2) Realizing I needed a new health care provider or medication change” (10%); (3) “Being told of the need for monitoring but no counseling/treatment change” (16%); and (4) “Being told everything is fine and there is nothing to worry about” (31%). Only half of the 61 cases reporting elevated HbA1c levels at screening experienced their PCP’s as responding with counseling or medication changes. Almost a third of cases perceived that their PCP’s dismissed the results, making no recommendations, and the rest perceived no counseling or interventions being proposed. Based on subjects’ perceptions of their PCP’s responses to their elevated HbA1c values, the impact of this intervention is substantially reduced over expectations.

Prenatal x-ray exposure may increase risk of schizophrenia: Results from the Jerusalem perinatal cohort schizophrenia study

ABSTRACT The purpose of this article is to determine the risk of schizophrenia in offspring of women exposed to x-ray radiation during pregnancy. The risk of schizophrenia was evaluated using cohort data collected in The Jerusalem Perinatal Study. The cohort of 92,408 births from 1964 to 1976 was linked to Israel’s National Psychiatric Registry of all individuals hospitalized for psychiatric conditions. Cross-tabulations were analyzed for development of schizophrenia in offspring of mothers who were exposed to an x-ray procedure during the first four months of pregnancy. Relative risks (RRs) were estimated using proportional hazards models, adjusted for male sex, paternal age, family psychiatric history, and social class. The adjusted RRs for schizophrenia spectrum associated with maternal x-rays in months 3 and 4 were, respectively, 2.97 (0.94–9.35) and 1.23 (0.39–3.87). Among 80 cases with narrowly defined schizophrenia (ICD-10u2009=u2009F20) maternal x-rays in months 3 and 4 were associated, respectively, with adjusted RRs of 3.08 (0.75–12.6, based on 2 cases), and 2.04 (0.64–6.46, 3 cases). Offspring of mothers exposed to x-ray radiation during the third and fourth months of pregnancy may have an increased risk of developing schizophrenia.